Hypertension Down Regulates Emilin1 In The Extracellular Matrix Of Resistance Arteries In Humans And Mice, In Order To Increase The Myogenic Tone Through Overactive Tgf Beta, Thus Contributing To Blood Pressure Regulation

Emilin1, a protein of the extracellular matrix of vessels, regulates TGFβ activity through proteolysis of the proTGFβ. Emilin1 KO mice, displaying increased TGFβ vascular activation, are hypertensive. As vascular Emilin1 is expressed from embryonic life to adulthood, we questioned whether the hypertensive phenotype results from a developmental defect or lack of a homeostatic role exerted in the adult. Thus, we inactivated Emilin1 in smooth muscle cells (VSMCs) of adult mice, with a tamoxifen inducible Cre -loxP, under the control of the SM myosin heavy chain promoter, finding that mice developed hypertension (HTN) as well as increased myogenic tone (MT) in resistance arteries. In order to evaluate the relevance of this mechanism in the human pathology, we enrolled 20 hypertensive (HT) and 20 normotensive (NT) patients, subjected to primary lumbar hernia neurosurgery, and dissected out resistance arteries from adipose tissue biopsies. We randomized vessels to receive vehicle, neutralizing antibody anti-TGFβ or non-relevant IgG and analyzed the MT. HT had a significantly increased MT, as compared to NT, rescued by the pretreatment with anti-TGFβ antibody. A pretreatment with the non-relevant IgG had no effect. Thus we hypothesized that Emilin1 could be down regulated by HTN to increase MT of resistances through overactive TGFβ, thus further sustaining high blood pressure (BP). In order to unravel this issue, we analyzed Emilin1 expression in the vessels walls of human arteries, finding a significant reduction in HT as compared to NT. We also evaluated Emilin1 expression in the resistance arteries of several murine models of HTN induced by: chronic AngII, DOCA-salt, L-NAME and obesity, finding that even in the experimental setting, HTN reduced Emilin1 in the vessel walls. Overall, we show that overactive TGFβ in VSMC increases the MT of resistance arteries, contributing to BP regulation. The data obtained in resistance arteries from HT and in the different murine models of HTN suggest that the down regulation of Emilin1 realized by HTN is a general mechanism to increase MT thus further sustaining high BP.